Nature encourages diversity in life forms (morphologies). The study of morphogenesis deals with understanding those processes that arise during the embryonic development of an organism. These processes control the organized spatial distribution of cells, which in turn gives rise to the characteristic form for the organism. Morphogenesis is a multi-scale modeling problem that can be studied at the molecular, cellular, and tissue levels. Here, we study the problem of morphogenesis at the cellular level by introducing an integrated biomechanical model of cells embedded in the extracellular matrix. The fundamental aspects of mechanobiology essential for studying morphogenesis at the cellular level are the cytoskeleton, extracellular matrix (ECM), and cell adhesion. Cells are modeled using tensegrity architecture. Our simulations demonstrate cellular events, such as differentiation, migration, and division using an extended tensegrity architecture that supports dynamic polymerization of the micro-filaments of the cell. Thus, our simulations add further support to the cellular tensegrity model. Viscoelastic behavior of extracellular matrix is modeled by extending one-dimensional mechanical models (by Maxwell and by Voigt) to three dimensions using finite element methods. The cell adhesion is modeled as a general Velcro-type model. We integrated the mechanics and dynamics of cell, ECM, and cell adhesion with a geometric model to create an integrated biomechanical model. In addition, the thesis discusses various computational issues, including generating the finite element mesh, mesh refinement, re-meshing, and solution mapping. As is known from a molecular level perspective, the genetic regulatory network of the organism controls this spatial distribution of cells along with some environmental factors modulating the process. The integrated biomechanical model presented here, besides generating interesting morphologies, can serve as a mesoscopic-scale platform upon which future work can correlate with the underlying genetic network.

Schistosomiasis is one of the most widespread parasite diseases in the world, whereas Schistosoma mansoni is a major schistosome species in Africa, America, and the Caribbean islets. Many antigenic vaccine candidates have been postulated, including sm22.6 and GST. Although the lower level of re-infection of human schistosomiasis is related to the higher level of IgE against rsm22.6, unfortunately, the observation of the experimental vaccination in mice finds some difficulties in further development of vaccine. In addition, the biochemical and biophysical properties of the antigen are virtually unknown, thus the present study intends to characterize sm22.6 from biochemistry and cell biology. To do this, sm22.6 was expressed in E. coli (BL21DE3) and purified to homogeneity. Analyses of the recombinant protein showed that the antigen was highly hydrophobic and formed polymers readily as judged by both native and denatured electrophoreses. Because various technologies including NMR and DNA binding which had been applied to the study of the antigen generated vague results, we decided to express the antigen in human breast cancer cell (MDA-MB-435s) to locate in the subcellular compartments where the antigen is situated. Results showed that the antigen, not like the recombinant expressed in E. coli, located in both cellular fluids and membrane, suggesting that the antigen might not be a skeleton protein as predicted by proteomics.

Thesis (M. Sc)--York University, 2000. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 87-100). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pMQ59208.

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The cytoskeleton plays an important role in trafficking proteins and other macromolecular moieties throughout the cell. Viruses have been thought to depend heavily on the cytoskeleton for their replication cycles. However, studies, including one in our lab, found that some viruses are not inhibited by anti-microtubule drugs. This study was undertaken to evaluate the replication of viruses from several families in the presence of cytoskeleton-inhibiting drugs and to examine the intracellular localization of the proteins of one of these viruses, Sindbis virus, to test the hypothesis that alternate pathways are used if the cytoskeleton is inhibited. We found that Sindbis virus (Togaviridae, positive-strand RNA), vesicular stomatitis virus (Rhabdoviridae, negative-strand RNA), and Herpes simplex virus 1 (Herpesviridae, DNA virus) were not inhibited by these drugs, contrary to expectation. Differences in the localization of the Sindbis virus were observed, suggesting the existence of alternate pathways for intracellular transport.

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It is becoming clear that mechanical stimuli are critical in regulating cell biology; however, the short-term structural response of a cell to mechanical forces remains relatively poorly understood. We mechanically stimulated cells expressing actin-EGFP with controlled forces (0-20nN) in order to investigate the cell’s structural response. Two clear force dependent responses were observed: a short-term local deformation of actin stress fibres and a long-term force-induced remodelling of stress fibres at cell edges, far from the point of contact. We were also able to quantify strain dynamics occurring along stress fibres. The cell exhibits complex heterogeneous negative and positive strain fluctuations along stress fibres, indicating localized dynamic contraction and expansion. A ~50% increase in myosin contractile activity is apparent following application of 20nN force. Directly visualizing force-propagation and stress fibre strain dynamics has revealed new information about the pathways involved in mechanotransduction which ultimately govern the downstream response of a cell.

Thesis (Ph. D.)--University of Virginia, 2000. / Spine title: Palladin & actin organization. Includes bibliographical references (leaves 209-251). Also available online through Digital Dissertations.

Thesis (M.S.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains ix, 138 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 93-94).